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Discovery and development of 2-aminobenzimidazoles as potent antimalarials.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Oct 05; Vol. 221, pp. 113518. Date of Electronic Publication: 2021 May 13. - Publication Year :
- 2021
-
Abstract
- The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC <subscript>50</subscript> values against P. falciparum 3D7 strain of 42 ± 4 (3c) and 43 ± 2 nM (3g), and high potency against strains resistant to chloroquine (Dd2), artemisinin (Cam3.II <superscript>C580Y</superscript> ) and PfATP4 inhibitors (SJ557733), while demonstrating no cytotoxicity against human cells (HEK293, IC <subscript>50</subscript>  > 50 μM). The most potent molecule, possessing a 4,5-dimethyl substituted phenol (3r) displayed an IC <subscript>50</subscript> value of 6.4 ± 0.5 nM against P. falciparum 3D7, representing a 12-fold increase in activity from the parent molecule. The 2-aminobenzimidazoles containing a N <superscript>1</superscript> -substituted phenol represent a new class of molecules that have high potency in vitro against P. falciparum malaria and low cytotoxicity. They possessed attractive pharmaceutical properties, including low molecular weight, high ligand efficiency, high solubility, synthetic tractability and low in vitro clearance in human liver microsomes.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antimalarials chemical synthesis
Antimalarials chemistry
Benzimidazoles chemical synthesis
Benzimidazoles chemistry
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Molecular Structure
Parasitic Sensitivity Tests
Structure-Activity Relationship
Antimalarials pharmacology
Benzimidazoles pharmacology
Drug Discovery
Malaria, Falciparum drug therapy
Plasmodium falciparum drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 221
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34058708
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113518